P1015: DURATION OF TREATMENT AND REDUCTION IN SERUM TRYPTASE LEVELS IN PATIENTS WITH ADVANCED SYSTEMIC MASTOCYTOSIS TREATED WITH AVAPRITINIB VERSUS BEST AVAILABLE THERAPY
Authors: A. Reiter, J. Gotlib, I. Álvarez-Twose, D. H. Radia, J. Luebke, P. J. Bobbili, A. Wang, C. Norregaard, S. Dimitrijević, E. Sullivan, M. Louie-Gao, J. Schwaab, I. A. Galinsky, C. Perkins, W. R. Sperr, P. Sriskandarajah, A. Chin, S. R. Sendhil, M. S. Duh, P. Valent, D. J. DeAngelo
Journal: HemaSphere (2022)

Background: Avapritinib, a selective and highly potent KIT D816V inhibitor, was approved in the United States (US) for treatment of adults with advanced systemic mastocytosis (AdvSM) based on results from two single-arm trials: EXPLORER (Phase 1; NCT02561988) and PATHFINDER (Phase 2; NCT03580655). There is no comparative response data for avapritinib versus best available therapy (BAT) for AdvSM. Aims: This study (NCT04695431) compared duration of treatment (DOT) and maximum reduction in serum tryptase levels between patients treated with avapritinib at a starting dose ≤200mg versus BAT. Methods: A multi-center, global, observational, retrospective chart review study was conducted at 6 study sites (4 European, 2 US) to identify and collect data from AdvSM patients who received BAT. Patients were identified using inclusion/exclusion criteria similar to EXPLORER and PATHFINDER trials. AdvSM patients receiving BAT could contribute data on multiple lines of therapy (LOT); these data were compared with patient data from the trials. DOT was defined as time from initiation to discontinuation of each LOT. Maximum reduction in serum tryptase on treatment was defined during each LOT. DOT was compared between cohorts using a Cox proportional hazards model and reduction in serum tryptase levels was compared using a generalized estimating equation linear model. Both models were weighted by inverse probability of treatment weights (IPTW) to adjust for confounding by key variables: age, sex, region, AdvSM subtype, anemia, thrombocytopenia, leukocyte count, skin involvement, number and type of prior treatments, performance status, serum tryptase level, and presence of SRSF2/ASXL1/RUNX1 mutations. Both models further adjusted for key covariates that remained unbalanced after weighting. Subgroup analyses were conducted in patients who received ≥1 prior LOT (2L+), and a 200mg starting dose of avapritinib. Results: The DOT analysis included 136 avapritinib patients and 137 BAT patients. Median (range) age for avapritinib and BAT patients was 68 (31−88) and 69 (21−88) years, and 59% versus 66% of patients were male, respectively. In the avapritinib group, 67%, 17%, and 16% of patients were diagnosed with SM with an associated hematological neoplasm (SM-AHN), aggressive SM (ASM), and mast cell leukemia (MCL), respectively, while in the BAT group, 55%, 29%, and 16% were diagnosed with SM-AHN, ASM, and MCL. Among 188 BAT LOTs with agent-level data available, most common treatments were midostaurin (53%) and cladribine (24%). Median DOT was 32.1 months (95% CI: 23.8, not estimable) for avapritinib and 5.5 months (95% CI: 5.1, 7.0) for BAT. In IPTW-weighted Cox analysis, DOT was significantly longer for avapritinib versus BAT (hazard ratio [95% CI]: 0.35 [0.23, 0.51]; P<0.001). The analysis of reduction in serum tryptase included 135 avapritinib and 116 BAT patients. Unadjusted maximum percentage reduction in serum tryptase levels was -84.8% (standard deviation [SD]: 19.9%) for avapritinib versus -9.2% (SD: 161.4%) for BAT. The adjusted mean difference in maximum percentage reduction in serum tryptase comparing avapritinib to BAT was -69.8% (95% CI: -89.4%, -50.2%; P<0.001). Results were similar in subgroups (Table 1). Image:Summary/Conclusion: AdvSM patients treated with avapritinib experienced significantly longer DOT and greater reduction in serum tryptase levels compared to patients treated with BAT. In the absence of RCTs, these data offer important and meaningful insight into the improved effectiveness of avapritinib compared to alternative therapies for AdvSM.